This project fulfills the NIDA/CEBRA criteria because it provides a novel approach to evaluate potential risks of exposure to drugs of abuse during early pregnancy. The project utilizes early sea urchin embryos as a model system, using a pharmacologic perturb-and-rescue strategy. This animal model represents a sensitive, high-throughput biosensor system for screening effects of drugs and neurotoxicants on early embryonic development. The project investigates effects of prenatal exposure to psychoactive drugs because of accumulated evidence that a variety of neurotransmitters are necessary for early development of sea urchin embryos, prior to the appearance of a nervous system ("pre-nervous neurotransmitters"), and evidence that these functions are mediated by receptors and carrier-mediated transporters similar to those found in the mammalian nervous system. It focuses on cannabinoids because of 1) previous reports that these substances play roles in fertilization and early mouse development, and 2) preliminary evidence that the cannabinoid, anandamide regulates early sea urchin development, mediated by CB1 receptors and carrier mediated transporters. The Specific Aims are designed to identify key components of the pre-nervous cannabinoid system, including receptors and transporters, and to characterize developmental dynamics of this system, using immunochemical and biochemical approaches. We will determine cell phenotype changes evoked by cannabinoids and search for potential antidotes to prevent them, including new lipophilic cannabinoid receptor antagonists. It is anticipated that these studies will provide insights into potential therapeutic strategies to prevent deleterious effects of prenatal cannabinoid exposure. Future studies will test these therapeutic strategies in the mouse.